|CCSVI||Chronic cerebrospinal venous insufficiency|
|ECD||Echo color Doppler|
|IJV||Internal jugular vein|
|DCV||Deep cerebral veins; includes internal cerebral vein, basal vein, Galen vein|
|RR||Relapsing remitting, secondary progressive, primary progressive; they are, respectively, the 3 main clinical course of MS|
|EDSS||Expanded disability status scale|
|MSFC||Multiple sclerosis functional composite, a score for expressing in a unique Z score the motor function of the upper and lower limb, and the cognitive function|
|VAS||Visual analog scale for postoperative pain assessment|
|Aim of physiologic cerebral venous drainage||To permit, by a monodirectional flow, a drainage of a volume of blood per unit of time adequate to the central nervous system. In CCSVI associated to MS the mean transit time calculated in magnetic resonance perfusion study is prolonged.|
|Reflux||Venous flow reversal to the physiologic direction for a duration >0.88 seconds in the extracranial pathways, and >0.50 seconds in the DCVs. Reflux in the present study was assessed in different body postures and never under Valsalva maneuver.|
- 1reflux in the IJVs or in the VV, or both with the head in any position;
- 2reflux in the deep cerebral veins;
- 3high-resolution B-mode evidence of IJV stenoses;
- 4flow not detected by Doppler in the IJVs or VVs, or both; and
- 5reverted postural control of the main cerebral venous outflow pathways,
Patients and methods
- •Relapse, disease progression, and steroid treatment in the 30 days preceding study entry (all conditions significantly modify clinical parameters, rendering unreliable any postoperative assessment);
- •Pre-existing medical conditions known to be associated with brain pathology, including neurodegenerative disorder, cerebrovascular disease, and history of alcohol abuse;
- •abnormal renal function; and
- •refusal to undergo the endovascular treatment.
Hemodynamic study of cerebrospinal venous drainage
- •Annulus refers to significant circumferential stenosis of the whole venous wall.
- •Septum/valve malformation refers to anomalous valve apparatus causing significant flow obstacles at the level of the IJVs junction with the brachiocephalic/anonymous trunk.
- •Hypoplasia refers to underdeveloped long venous segments.
- •Twisting refers to severe stenoses in consequence of a twisted venous segment.
- •Membranous obstruction refers to a membrane almost occluding a vein.
- •Agenesis refers to the complete anatomic absence of a venous segment
PTA of the AZY and IJV
Vascular outcome measures
- 1venous pressure expressed in cm H2O measured preoperatively and postoperatively by means of a manometer in the superior vena cava, in the AZY, and in both IJVs;
- 2the postoperative course and rate of complications; in particular, we assessed patients' tolerance to the procedure, investigated pain by the means of the validated visual analogue scale (VAS),20and also postoperative thrombosis, major and minor bleeding, and adverse effects from contrast media; and
- 3patency rate by using a ECD surveillance at 1, 3, 6, 12, 15, and 18 months, assessing the same preoperative variables.4,6At the end of the 18 months of follow-up, patients with ECD-suspected restenosis underwent venography as well as an eventual second PTA treatment
- 1Disease severity. When a treatment evaluation is contemplated, MS severity should be scored by means of the Multiple Sclerosis Functional Composite (MSFC)21,22instead of the widely used but insufficiently detailed EDSS.17The MSFC gives the comprehensive index Z for scoring the motility of upper and lower extremities as well as cognitive function (Appendix, online only). The same physician (A. M.) performed the MSFC preoperative and postoperative assessment always at the same hour and in the same location and condition.
- 2Relapse in RR patients. This clinical variable is expressed by the proportion of patients who were relapse-free at 1 year and by the annualized relapse rate compared with that reported during the 2 years preceding PTA.23,24,25
- 3Quality of life (QOL). This was evaluated by using a validated 54-item questionnaire, the Multiple Sclerosis Quality of Life-54 Instrument, addressed to MS patients and subdivided in two parts evaluating physical and mental status.26
|Variable||All patents (n = 65)||MS progression|
|RR (n = 35)||SP (n = 20)||PP (n = 10)|
|Age, y||41.7 ± 12.2||34.8 ± 8.3||46.8 ± 9.7||55.6 ± 12.2|
|MSFC||−0.0003 ± 0.6||5.5e-18 ± 0.7||0 ± 0.8||−0.001 ± 0.5|
|EDSS||3 ± 2.3||1.7 ± 0.9||5 ± 2.2||4.7 ± 2|
|Disease duration, y||8.6 ± 7.1||5.1 ± 4.4||14 ± 7.8||9.3 ± 6.3|
Feasibility and safety of the procedure
Results of selective venography
- Type A pattern (30%) is characterized by significant stenosis of the proximal AZY or of one of the two IJVs, with a compensatory contralateral IJV that appears with an ample cross-sectional area; it was observed in 10 of 35 RR patients, in five of 20 SP patients, but never in PP patients.
- Type B pattern (38%) is characterized by significant stenoses of both IJVs and the proximal azygous; it was observed in 19 of 35 RR patients, in nine of 20 SP patients, and in one of 10 PP patients.
- Type C pattern (14%) is characterized by bilateral stenosis in both IJVs, with a normal AZY system; it was observed in four of 35 RR patients, in five of 20 SP patients, but never in PP patients.
- Type D pattern (18%) is characterized by the multilevel involvement of the AZY and lumbar systems. Association with the IJVs was observed in approximately 50% and caused an additional obstruction in these patients. It was observed in two of 35 RR patients, in one of 20 SP patients, and in nine of 10 PP patients.
|Location||Normal segment||Annulus||Septum/valve malformation||Hypoplasia|
|Distal AZY, No.|
- •Disease severity: In RR patients, the MSFC showed highly significant improvement at 18 months (P < .008; Table IV). MSFC showed significant although limited improvement after the first 6 months in both PP and in SP clinical courses, but at 18 months showed no improvement respect to baseline (Table V).Table IVPreprocedural and postprocedural changes in clinical, magnetic resonance imaging, quality of life, and disability scale in relapsing remitting patients
Variable Pre-PTA 18-month FU P Annualized relapse rate 0.9 ± 0.8 0.7 ± 1 .11 Patients free of relapse, % 27 50 <.0014 Patients with MRI Gad+ lesions, %a 50 12 <.0001 MSQOL PHC, mean ± SDb 66 ± 18 84 ± 16 .0097 MSQOL MHC, mean ± SDc 61 ± 22 82 ± 13 .003 MSFC, mean ± SDd 5.5e-18 ± 0.7 0.65 ± 0.5 .0085.5e-, Infinitesimal negative baseline value of the MSFC; FU, follow-up; NS, not significant; PTA, percutaneous transluminal angioplasty.a Magnetic resonance imaging-active gadolinium-enhanced lesions.b MSQOL PHC: Score of physical health component of the Multiple Sclerosis Quality of Life 54-item Instrument.c MSQOL MHC: Score of mental health component of the Multiple Sclerosis Quality of Life 54-item Instrument.d MSFC: Multiple Sclerosis Functional Composite a disability scale expressed by the Zeta score, which integrates evaluation of the motility of the upper and lower extremities with cognitive function.Table VPreprocedural and postprocedural changes in measure of quality of life and of disability in secondary progressive (SP) and primary progressive patients (PP) Status Pre-PTA 18-month FU P SP MSQOL PHCa 47 ± 12 62 ± 16 <.08 MSQOL MHCb 65 ± 3 70 ± 18 >.10 MSFCc 0 ± 0.8 0.5 ± 0.6 >.10 PP MSQOL PHC 53 ± 13 66 ± 12 <.03 MSQOL MHC 60 ± 15 78 ± 9 <.01 MSFC −0.001 ± 0.5 0.04 ± 0.6 >.10FU, Follow-up; NS, not significant; PP, primary progressive course; PTA, percutaneous transluminal angioplasty; SP, secondary progressive course.a MSQOL PHC: Score of physical health component of the Multiple Sclerosis Quality of Life 54-item Instrument.b MSQOL MHC: Score of mental health component of the Multiple Sclerosis Quality of Life 54-item Instrument.c MSFC: Multiple Sclerosis Functional Composite, a disability scale expressed by the Zeta score, which integrates evaluation of the motility of the upper and lower extremities with cognitive function.
- •Relapse in RR patients: The rate of patients who were relapse-free in the year preceding endovascular treatment was only 27%, highly significantly different from the 50% assessed in the postoperative outcome (Table IV), whereas the annualized relapse rate (comparing rate of relapse before and after PTA) was not significantly different in the RR patients (Table IV). Finally, all RR patients with postprocedural patency of the IJVs and AZY were always relapse-free.
- •MRI outcome measure: The rate of patients with active gadolinium-enhanced lesions at MRI decreased significantly from 50% to 12% (P < .0001; Table IV.
- Havrdova E.
- Galetta S.
- Hutchinson M.
- Stefoski D.
- Bates D.
- Polman C.H.
- et al.
- Conception and design: PZ, FS
- Analysis and interpretation: PZ, RG, FS
- Data collection: PZ, RG, EM, AM, SG, IB, FS
- Writing the article: PZ, RG, AM
- Critical revision of the article: PZ, RG, FM, FS
- Final approval of the article: PZ, RG, EM, AM, SG, IB, FM, FS
- Statistical analysis: PZ, AM
- Obtained funding: PZ, FM
- Overall responsibility: PZ
- Video 1
- Video 2
Appendix (online only). Neurologic and Doppler outcome parameters
1. Revised McDonald Criteria
- •At least two attacks with objective clinical evidence of at least two lesions;
- •At least two attacks with objective clinical evidence of one lesion plus dissemination in space shown on magnetic resonance imaging (MRI), or two or more MRI lesions consistent with MS plus positive cerebrospinal fluid (CSF) finding or second clinical attack;
- •One attack with objective clinical evidence of at least two lesions plus dissemination in time on MRI or a second clinical attack;
- •One attack with objective clinical evidence of one lesion, plus dissemination in space shown on MRI or two or more MRI lesions consistent with MS plus positive CSF finding and dissemination in time shown on MRI or second clinical attack;
- •Insidious neurologic progression suggestive of MS plus 1 year of disease progression determined retrospectively or prospectively and two of the following: positive brain MRI result (nine T2 lesions or at least four T2 lesions with positive visual evoked potential), positive spinal cord MRI result with two focal T2 lesions, and positive CSF findings.
- 1one or more gadolinium-enhancing lesions or nine T2 hyperintense lesions;
- 2one or more infratentorial lesions; one or more juxtacortical lesions;
- 3or three or more periventricular lesions.
2. Expanded Disability Status Scale
- •Pyramidal (ability to walk);
- •Cerebellar (coordination);
- •Brain stem (speech and swallowing);
- •Sensory (touch and pain);
- •Bowel and bladder functions;
- •Other (includes any other neurologic findings due to MS).
- •EDSS 1.0-3.0: Able to do regular activities normally.
- •EDSS 3.5-4.5: Moderate disability that starts to impair daily functioning.
- •EDSS 5.0-5.5: Unable to do full daily activities, but still able to walk without assistance.
- •EDSS 6.0-6.5: Needs assistance to walk, such as a cane, crutch, or brace.
- •EDSS 7.0-8.0: Needs a wheelchair most of the time but may still be able to walk a few steps around the home with assistance.
- •EDSS 8.5-9.5: Bedridden most of the day; may have lost use of arms and ability to communicate effectively or eat.
- •EDSS 10.0: Death due to MS.
3. Multiple Sclerosis Functional Composite
- •T25FW: Patients were instructed to walk 25 feet as quickly as possible, but safely. The average time of two consecutive trials was recorded.
- •9-HPT: Patients were instructed to pick up nine pegs one at a time as quickly as possible and put them in a block containing nine empty holes, and once they were in the holes, to remove them again as quickly as possible one at a time. The dominant and nondominant hands were both tested twice, and the average time for each hand was recorded.
- •PASAT: The test was presented using a voice recording. Patients had to add a sequence of numbers presented every 3 seconds, each new one to the one immediately before it. The number of correct sums was recorded.
4. Echo color Doppler for investigation of cerebral venous return
- •Patient position: The posture of the individual being examined by echo color Doppler (ECD) is crucial in determining the main route of cerebral outflow. For this reason, the person should be investigated at least in both supine and sitting positions (0° and 90°). This objective can be realized with the individuals being positioned on a tilt bed or chair.5,6,7
- •Equipment and transducers: The investigation of the cerebral venous hemodynamics can envisage the contemporaneous analysis of both the intracranial and extracranial pathways by combining with the same ultrasound machine, respectively, the examination of the deep cerebral veins (DCVs) with that of the internal jugular veins-vertebral veins (IJVs-VVs) by means of the proper ultrasound probe. The transducer at the intracranial level is at low frequency, usually ≤2.5 Mhz, whereas a high frequency, 6- to 13-Mhz, linear or microconvex probe is used at the cervical level, according to the different depth of the veins respective to the body surface where the transducer is placed.5,6,7
- •DCVs flow direction assessment: The transducer is placed at the level of the transtemporal bone window, and the depth of the insonation is adjusted to 10 cm. At an insonation depth of about 6 to 7 cm, it is possible to consistently identify the echolucent third ventricle, limited by two echogenic bright margins, as well as the two comma-shaped frontal horns of the lateral ventricles. Individuals can be examined both in sitting and supine positions, and the venous flow is enhanced by inviting the person to breathe, and setting the pulse repetition frequency of the instrument to lower values, ranging between 0.3 and 1.4. By using the transtemporal acoustic bone window, it is possible to insonate around the third ventricle at least one of the DCVs, or all three branches, including basal veins of Rosenthal (flow expected upward and toward the Galen vein), great vein of Galen (flow expected toward the occipital side into the straight sinus), and internal cerebral veins (flow expected downward and toward the Galen vein). Reflux is a reverse flow for a duration >0.5 seconds.5,6,7
- •IJVs-VVs flow direction assessment: Examination is performed with high-frequency transducers as above reported. Individuals should be examined at least in sitting and supine positions. Flow recording begins 2 minutes after the change in posture and after several deep breaths to permit blood redistribution in the venous system. For each assessment, the direction of flow is analyzed either with the pulsed-wave mode and the sample placed in the vessel at a 60° angle, or with the color-coded mode by comparing the color of the flow in the IJV-VV with that of the satellite carotid or vertebral artery, or both, respectively. Either the IJVs or the VVs can be examined by using the transversal or the longitudinal cervical access, or both. The operator uses minimal pressure over the skin to prevent compressing the vein and thereby affecting the measurement. Flow direction is normally directed toward the heart. Reflux is a reverse flow assessed in the respiratory pause for a duration >0.88 seconds.5,6,7
- •Assessment of cross-sectional area: The level of IJV insonation corresponds to the thyroid gland, and the point of measurement is outlined over the skin with a waterproof pen. The individual is examined in sitting and supine positions using the transversal access (by the longitudinal scan, the operator is unaware if the cross-sectional area [CSA] is elliptical or circular, thus affecting the measurement). The operator uses minimal pressure over the skin to prevent compressing the vein and thereby affecting the measurement. CSA is measured in the supine and sitting positions by means of the software for elliptical or circular shapes included in the ECD instrumentation, separately in the right and left IJV. Alternatively, it is possible to measure the diameter by means of the software and to calculate the CSA according to geometric formulas, respectively, for circle and ellipse. In case of spontaneous fluctuations in CSA caused by activation of the thoracic pump, the CSA can be measured during a short period of apnea after a normal exhalation. The CSA is calculated by subtracting the CSA measured in the supine position from that in the erect position, separately in the right and left IJV.5,6,7
- •B-mode anomalies. Malformations in the IJVs often correspond to the presence of septum/valve malformation at the level of the proximal segment of these veins.5,6,7They hamper the venous flow, causing turbulences, or determine blocked flow or reflux, especially during inspiration, with a paradoxic functional obstruction in the more favorable condition for venous emptying (activation of the thoracic aspiration). Videos 1 and 2 provide exemplification of the more frequent B-mode anomalies.
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